Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Journal: Nature
Published:
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Authors
Luke Jostins, Stephan Ripke, Rinse Weersma, Richard Duerr, Dermot Mcgovern, Ken Hui, James Lee, L Schumm, Yashoda Sharma, Carl Anderson, Jonah Essers, Mitja Mitrovic, Kaida Ning, Isabelle Cleynen, Emilie Theatre, Sarah Spain, Soumya Raychaudhuri, Philippe Goyette, Zhi Wei, Clara Abraham, Jean-paul Achkar, Tariq Ahmad, Leila Amininejad, Ashwin Ananthakrishnan, Vibeke Andersen, Jane Andrews, Leonard Baidoo, Tobias Balschun, Peter Bampton, Alain Bitton, Gabrielle Boucher, Stephan Brand, Carsten Büning, Ariella Cohain, Sven Cichon, Mauro D'amato, Dirk De Jong, Kathy Devaney, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Lynnette Ferguson, Denis Franchimont, Karin Fransen, Richard Gearry, Michel Georges, Christian Gieger, Jürgen Glas, Talin Haritunians, Ailsa Hart, Chris Hawkey, Matija Hedl, Xinli Hu, Tom Karlsen, Limas Kupcinskas, Subra Kugathasan, Anna Latiano, Debby Laukens, Ian Lawrance, Charlie Lees, Edouard Louis, Gillian Mahy, John Mansfield, Angharad Morgan, Craig Mowat, William Newman, Orazio Palmieri, Cyriel Ponsioen, Uros Potocnik, Natalie Prescott, Miguel Regueiro, Jerome Rotter, Richard Russell, Jeremy Sanderson, Miquel Sans, Jack Satsangi, Stefan Schreiber, Lisa Simms, Jurgita Sventoraityte, Stephan Targan, Kent Taylor, Mark Tremelling, Hein Verspaget, Martine De Vos, Cisca Wijmenga, David Wilson, Juliane Winkelmann, Ramnik Xavier, Sebastian Zeissig, Bin Zhang, Clarence Zhang, Hongyu Zhao, Vito Annese, Hakon Hakonarson, Steven Brant, Graham Radford Smith, Christopher Mathew, John Rioux, Eric Schadt, Mark Daly, Andre Franke, Miles Parkes, Severine Vermeire, Jeffrey Barrett, Judy Cho